ObjectiveTo analyze the incidence and influencing factors of cardiovascular disease （CVD） in uremia patients after combined blood purification therapy.MethodsClinical data of uremia patients admitted to Putuo People's Hospital， Tongji University from January 1， 2021 to January 31， 2023 were retrospectively analyzed. All patients received combined blood purification treatment （hemodialysis + hemoperfusion + hemodialysis filtration）. They were divided into the CVD group and non-CVD group based on the presence or absence of CVD at 12 months of treatment. The general demographic data and clinical data of the two groups were compared. Logistic regression model was used to analyze the influencing factors of CVD occurrence after combined blood purification， and Spearman correlation analysis was used to analyze the correlation between each factor and CVD occurrence.ResultsA total of 122 uremia patients were included in the study， of which 20 had CVD， accounting for 16.39%， and the remaining 102 （83.61%） without CVD were included in the non-CVD group. Logistic regression analysis showed age， treatment time， CVD history， soluble Fas ligand （sFasL） expression in serum and soluble cardiac troponin T （cTnT） before treatment， human advanced oxidation protein products （AOPP）， serum ferritin （SF）， serum hemoglobin （Hb）， parathyroid hormone （PTH） and calcium-phosphorus product were all factors affecting the development of CVD after combined blood purification. OR values were 1.270， 1.938， 13.800， 46.984， 1.270， 8.522， 2.145， 1.495， 1.733， and 1.528， respectively. Age， treatment time， CVD history， serum sFasL expression， average cTnT， AOPP， PTH， calcium and phosphorus product before treatment were positively correlated with CVD occurrence （r=0.471， 0.643， 0.589， 0.485， 0.647， 0.499， 0.528， and 0.492， respectively； all P<0.05）. SF and Hb were negatively correlated with CVD （r=-0.505， and -0.478， respectively； both P<0.05）.ConclusionCVD occurs in some uremia patients after combined blood purification treatment. Age， treatment time， CVD history， serum sFasL expression， average cTnT， AOPP， SF， Hb， PTH and calcium-phosphorus product before treatment are the influencing factors for cardiovascular prognosis， which are related to the occurrence of CVD. It is necessary to pay close attention to patients with old age， long treatment time and history of CVD， and strengthen the detection of serum sFasL， cTnT， AOPP， SF， Hb， PTH and calcium and phosphorus product， which can provide theoretical basis for clinical diagnosis and prevention of CVD， and thus improve the cardiovascular prognosis of patients.

BACKGROUND:The impact of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), including dapagliflozin, on the renin-angiotensin-aldosterone system (RAAS) in type 2 diabetes mellitus (T2DM) patients remains controversial, as they may either activate or inhibit RAAS, subsequently influencing glucose metabolism and the accuracy of the aldosterone-to-renin ratio (ARR) in diagnosing primary aldosteronism (PA). However, the effects of SGLT-2is therapy on RAAS and their correlation with glucose metabolism have not been well studied. METHODS:A cohort of 147 patients with T2DM and hypertension was prospectively recruited and categorized into two groups: diabetic kidney disease group (DKD, n = 73) and non-DKD group (n = 74), based on diagnostic criteria for diabetic complications. Patients were prescribed 10 mg dapagliflozin daily for 3 months. The primary outcome measure was the change in renin (REN) levels during outpatient visits at baseline, 1 month, and 3 months. The secondary outcome was the change in other metabolic biomarkers from baseline to the 3-month visit. To evaluate the relationship between RAAS components and various glucose metabolism indicators, including HbA1c, FBG, CP, HOMA-β, HOMA-IR, and UACR, Spearman correlation and multiple linear regression analyses were conducted at baseline and 3-month visit. RESULTS:After 3 months, the BMI, HbA1c, FBG, TG, TCHO, SBP, DBP, UACR, and HOMA-IR levels were significantly decreased, while Crea and HOMA-β were significantly increased from the baseline in both groups. Additionally, the differences from the baseline in FBG (-2.64 ± 2.66 vs. -1.70 ± 1.92 mmol/L) and UACR (-355.01 ± 1534.12 vs. -4.66 ± 7.86 mg/g) values were significantly higher in DKD group than those in non-DKD group. REN levels increased significantly from baseline at 1-month visit (4.15 ± 7.35 vs. 2.75 ± 8.03 ng/L; DKD vs. non-DKD; between-group difference, p < 0.05), while ARR values decreased significantly from baseline at 1-month visit (-0.70 ± 1.16 vs. -0.59 ± 1.19; between‑group difference, p > 0.05) and 3-month visit (-0.45 ± 1.15 vs. -0.42 ± 1.07; between‑group difference, p > 0.05) in both groups (within‑group change vs. baseline, p < 0.017). Interestingly, no temporal differences were observed in ALD levels. REN levels returned to baseline after three months of treatment; yet the ARR, which was primarily influenced by REN, remained below its initial value. Multiple linear regression analysis revealed that a 100% increase in Log-ALD was associated with a 0.143 nmol/L higher CP and a 15.8% higher HOMA-IR in DKD group(p < 0.05). A 100% increase in Log-REN was associated with a 0.359 mg/g lower UACR in DKD group and a 0.042 mmol/L higher FBG in non-DKD group(p < 0.01). These correlations were independent of the internal interactions of RAAS but were significantly attenuated after 3 months of treatment. CONCLUSIONS:The correlations between RAAS markers and glucose metabolism indices were significantly attenuated, potentially due to lowered blood glucose levels after SGLT‑2is treatment. However, it is noteworthy that short-term therapy may elevate REN levels and reduce ARR, potentially resulting in false-negative outcomes in PA screening.

Diabetic kidney disease (DKD) is characterized by abnormal metabolic profiles. Metabolomics reveals increased serum levels of 3-phosphoglycerate (3-PG) in DKD patients. The protein expression of phosphoglycerate kinase 1 (PGK1), a key rate-limiting enzyme for 3-PG synthesis, is concomitantly upregulated in DKD patients and mice. The development of DKD is significantly mitigated by renal tubular epithelial cell-specific knockout of PGK1 and robustly worsened by PGK1 overexpression. Mechanistically, PGK1-dependent enzymatic production of 3-PG facilitates DKD through inhibiting GPX1 to activate the NLRP3 inflammasome. PGK1 promotes UNC5CL-mediated inflammation by binding to aldehyde dehydrogenase-1 L1 (Aldh1l1) through its non-enzymatic activity. The transcription factor paired box protein 5 (PAX5) mediates the upregulation of PGK1 in DKD. High-throughput screening reveals that C-16 from ChemDiv, the natural product lirinidine, and the Food and Drug Administration (FDA)-approved oxantel pamoate are potent PGK1 antagonists and efficaciously prevent DKD. Overall, blocking PGK1 may be a promising avenue for DKD management.

BackgroundThe presence of hypertension and various acute or chronic complications may affect the renin-angiotensin-aldosterone system (RAAS) in patients with type 2 diabetes mellitus (T2DM), which plays a crucial role in the regulation of glucose metabolism. However, the quantitative distribution of the RAAS components in relation to the progression of T2DM and the treatment of hyperglycemia and hypertension, as well as their association with different stages of complications and glucose metabolism, has not been well studied.MethodsWe enrolled a total of 151 patients with T2DM and essential hypertension, 40 patients with T2DM and normotension, and 46 healthy controls in the study. They were categorized into subgroups based on criteria for diabetic complications. Statistical analyses, including Spearman rank correlation and multiple linear regression, were conducted to assess the relationship between RAAS components and glucose metabolism indexes such as HbA1c, FBG, CP, HOMA-β, HOMA-IR, and UACR.ResultsThe results revealed significant differences in AII, ALD, REN, and ARR levels across various complication subgroups. Notably, the concentrations of ALD and REN exhibited a consistent trend, while ARR showed an opposite trend to the REN concentration. More than 60% of hypertensive patients were treated with ACEI/ARBs and calcium channel blockers, while 29.8% of the patients were prescribed β-blockers, resulting in decreased REN and increased ARR levels. All T2DM patients received antidiabetic treatment, among which 95 (49.7%) took SGLT-2is, 40 (20.9%) took GLP-1RAs injection and 55(28.8%) took DPP-4is. The subsequent analysis revealed that SGLT-2is, GLP-1RAs, DPP-4is and other glucose-lowering agents had no statistically significant effect on the RAAS system (p > 0.05). The correlation matrix analysis indicated positive associations between ALD, REN, CP, and HOMA-IR. Furthermore, the REN levels were negatively correlated with UACR in the hypertensive group and positively correlated with HbA1c and FBG levels in the normotensive group. Multiple linear regression analysis demonstrated that ALD levels increased with higher levels of CP and HOMA-IR, independently of the RAAS system, anti-RAAS treatment and antidiabetic therapy. REN levels decreased with increasing UACR and β-blocker usage in the hypertensive group, while they increased with higher levels of HbA1c, FBG, and HOMA-IR in the normotensive group, independently of the RAAS system and antidiabetic therapy.ConclusionsThe activation status of the RAAS system varied among T2DM patients with different complications, highlighting the need for clinical differentiation. ALD was positively associated with insulin resistance and glucose metabolism impairment, while REN exhibited negative correlations with urinary microalbumin and β-blocker usage, and positive correlations with hyperglycemia and insulin resistance. Blocking the RAAS system holds promise for improving insulin sensitivity and β-cell function, and potentially reversing abnormal glucose tolerance or ameliorating glucose metabolism disorders.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and a growing public health problem worldwide. Losartan potassium (Los), an angiotensin II receptor blocker, has been used to treat DKD clinically. Recently, multi-herbal formula has been shown to exhibit therapeutic activities in DKD in China. Thus, we aimed to explore the protective effects of combination of Los and Qi-Bang-Yi-Shen formula (QBF) on DKD rats. Streptozotocin (STZ) injection was used to establish a rat model of DKD. Next, the bloodurea nitrogen (BUN), creatinine (CRE) and uric acid (UA) levels were detected in serum samples from DKD rats. Hematoxylin and eosin (H&E), periodic Acid Schiff (PAS) and Masson staining were performed to observe glomerular injury and glomerular fibrosis in DKD rats. In this study, we found that QBF or Los treatment could decrease serum BUN, CRE, UA levels and reduce urine albumin-to-creatinine ratio (ACR) in DKD rats. Additionally, QBF or Los treatment obviously inhibited glomerular mesangial expansion and glomerular fibrosis, attenuated glomerular injury in kidney tissues of DKD rats. Moreover, QBF or Los treatment significantly reduced PI3K, AKT and ERK1/2 protein expressions, but increased PPARγ level in kidney tissues of DKD rats. As expected, combined treatment of QBF and Los could exert enhanced reno-protective effects compared with the single treatment. Collectively, combination of QBF and Los could ameliorate renal injury and fibrosis in DKD rats via regulating PI3K/AKT, ERK and PPARγ signaling pathways. These findings highlight the therapeutic potential of QBF to prevent DKD progression.

Background Disability in activities of daily living (ADL) significantly increases the risk of mortality among patients undergoing hemodialysis. Malnutrition and decreased exercise capacity are closely correlated with ADL disability. Phase angle (PhA) has been proposed as a measure of nutritional status and exercise capacity. This study aims to investigate the prevalence of ADL disability in hemodialysis patients and its association with PhA. Methods A prospective, observational study was conducted, involving hemodialysis patients treated between November 2019 and January 2020 in an affiliated hospital of Chinese university. ADL was measured using both basic ADL (BADL) scales and instrumental ADL (IADL) scales. PhA measurements were obtained using a BIA device while the patients were in the supine position after dialysis. Results A total of 237 hemodialysis patients with a mean age of 60.01 ± 13.55 years were included in this study. The prevalence of disability in ADL was 43.5%. Multivariable analysis results showed a robust association between low PhA and disability in both BADL and IADL (for each unit decrease in PhA: odds ratio 4.83 [95% CI: 2.56–9.0], and 3.57 [95% CI: 2.14–5.95], respectively). The optimal cut-off values of PhA for disability in BADL and IADL were 4.8 and 5.4, with the area under the ROC curve (AUC) were 0.783 (0.727, 0.835) and 0.799 (0.743, 0.848), respectively. Conclusions Low PhA is strongly associated with disability in ADL in hemodialysis patients. These findings suggest that PhA may serve as a potentially objective measure of ADL disability in hemodialysis patients.

BACKGROUND:This retrospective study aimed to evaluate the diagnostic value of early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) in immunoglobulin A nephropathy (IgAN) associated with renal tuberculosis (RT). METHODS:Forty patients with IgAN (IgAN group), 32 patients with RT (RT group), and 52 patients with IgAN associated with RT (IgAN + RT group) were retrospectively selected for this study. A tuberculin skin test (TST) was conducted, and Mycobacterium tuberculosis (MTB) antibody levels were measured. Immunohistochemistry and western blotting were used to determine the expression of ESAT-6 and CFP-10 proteins in renal tissues. RESULTS:The positive results of TST and levels of serum and urinary MTB antibodies were higher in the RT group than in the IgAN + RT group. The expression levels of ESAT-6 and CFP-10 proteins were the highest in the IgAN + RT group and lowest in the IgAN group. The receiver operating characteristic curves indicated that the area under curve (AUC) value of the ESAT-6 protein for the diagnosis of IgAN associated with RT was 0.907 and the cut-off value of the integral optical density (IOD) was 26.72. Diagnosis based on ESAT-6 protein levels showed 75% sensitivity and 94.2% specificity. The AUC value of the CFP-10 protein for the diagnosis of IgAN associated with RT was 0.8 and the cut-off value of IOD was 25.67. Detection based on CFP-10 protein levels showed 63.9% sensitivity and 84.6% specificity. CONCLUSIONS:Our study provides evidence for the potential of ESAT-6 and CFP-10 proteins as candidate markers in the diagnosis of IgAN associated with RT.

Pathological heterogeneity is common in clinical tissue specimens and complicates the interpretation of molecular data obtained from the specimen. As a typical example, a kidney biopsy specimen often contains glomeruli and tubulointerstitial regions with different levels of histological injury, including some that are histologically normal. We reasoned that the molecular profiles of kidney tissue regions with specific histological injury scores could provide new insights into kidney injury progression. Therefore, we developed a strategy to perform small RNA deep sequencing analysis for individually scored glomerular and tubulointerstitial regions in formalin-fixed, paraffin-embedded kidney needle biopsies. This approach was applied to study focal segmental glomerulosclerosis (FSGS), the leading cause of nephrotic syndrome in adults. Large numbers of small RNAs, including microRNAs, 3'-tRFs, 5'-tRFs, and mitochondrial tRFs, were differentially expressed between histologically indistinguishable tissue regions from patients with FSGS and matched healthy controls. A majority of tRFs were upregulated in FSGS. Several small RNAs were differentially expressed between tissue regions with different histological scores in FSGS. Notably, with increasing levels of histological damage, miR-21-5p was upregulated progressively and miR-192-5p was downregulated progressively in glomerular and tubulointerstitial regions, respectively. This study marks the first genome scale molecular profiling conducted in histologically characterized glomerular and tubulointerstitial regions. Thus, substantial molecular changes in histologically normal kidney regions in FSGS might contribute to initiating tissue injury or represent compensatory mechanisms. In addition, several small RNAs might contribute to subsequent progression of glomerular and tubulointerstitial injury, and histologically mapping small RNA profiles may be applied to analyze tissue specimens in any disease.

OBJECTIVES To investigate the association of sarcopenia and its components (muscle mass, muscle strength, and physical performance) with dependency in activities of daily living (ADLs) in maintaining patients on hemodialysis. DESIGN AND METHODS This is a cross-sectional study. Sarcopenia was identified according to the Asian Working Group for Sarcopenia 2019 criteria. Basic ADLs (BADLs) and instrumental ADLs (IADLs) were assessed. Logistic regression was used to estimate the association of sarcopenia and its components with dependency. Area under the receiver-operating characteristic curve of gait speed corresponding with dependency was calculated. RESULTS A total of 238 patients on hemodialysis were included. The proportion of enrolled male candidates was 67.6%, and the average age was 60.9 years. In all, 49.2% (n = 117) and 30.7% (n = 73) of patients on dialysis were diagnosed with sarcopenia and severe sarcopenia, respectively. Dependency in BADLs was 21.0% (n = 50), and dependency in IADLs was 41.2% (n = 98). Severe sarcopenia was significantly associated with dependency in BADLs and IADLs after adjustment of clinical covariables (odds ratio [OR], 4.68 [95% confidence interval (CI): 2.11-10.40]; OR, 3.24 [95% CI: 1.61-6.53], respectively), whereas those effects for sarcopenia were not significant. With all three sarcopenia components in the analysis model, high gait speed remained strongly associated with low function dependency in BADLs and IADLs (per 0.1 m/s increase of gait speed: OR, 0.52 [95% CI: 0.41-0.66]; and 0.46 [95% CI: 0.35-0.59], respectively). Area under the receiver-operating characteristic curve of gait speed corresponding with dependency in BADLs and IADLs was 0.827 (0.759, 0.896) and 0.878 (0.832, 0.925), respectively. CONCLUSIONS Severe sarcopenia was closely related to dependency in ADL in patients on hemodialysis. Gait speed was the most important factor affecting dependency in sarcopenia and had good diagnostic accuracy for screening dependency in ADL.

Background: This study evaluated the diagnostic value of early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) in immunoglobulin A nephropathy (IgAN) associated with renal tuberculosis (RT). Methods: Between January 2013 and January 2016, 40 patients with IgAN (IgAN group), 32 patients with RT (RT group), and 52 patients with IgAN associated with RT (IgAN + RT group) were selected for this study. A Tuberculin skin test (TST) was conducted, and serum Mycobacterium tuberculosis ( MTB ) antibody levels were measured. Urine samples were collected to culture MTB . Immunohistochemistry and western blotting were used to determine the expression of ESAT-6 and CFP-10 in renal tissues. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic values of ESAT-6 and CFP-10 in IgAN associated with RT. Results: TST, serum MTB antibody, and urine MTB assessments were negative in the IgAN group. The positive rates of the TST and serum MTB antibody and urine MTB testing were higher in the RT group than in the IgAN + RT group. Among the three groups, expression levels of ESAT-6 and CFP-10 were found to be the highest in the IgAN + RT group and were found to be the lowest in the IgAN group. The ROC curves indicated that the area under curve (AUC) value of ESAT-6 protein for IgAN + RT diagnosis was 0.907 with a cut-off of 26.72 as the critical value. Detection by ESAT-6 protein levels achieved 75.0% sensitivity and 94.2% specificity. The AUC value of the CFP-10 protein for diagnosis of IgAN + RT was 0.800, with a cut-off of 25.665 as the critical value. Detection by the protein levels of CFP-10 showed 63.9% sensitivity and 84.6% specificity. Conclusions: Our study provides evidence for the potential of the proteins ESAT-6 and CFP-10 as candidate markers for the diagnosis of IgAN associated with RT.

Abstract Background and Aims Both constipation and chronic kidney disease (CKD) are common among seniors. However, the association between constipation and CKD remain unclear. This study investigates the correlation between the two to provide a new basis for clinical treatment. Method Data from Shanghai community elderly physical examination database (2010-2018) were used to conduct a cross-sectional study and a retrospective cohort to evaluate the relationship between constipation and the prevalence of CKD and rapid renal function decline in the elderly community. Results The cross-sectional study covered 16,177 participants, with an average age of 71.3. Comparing to no constipation group, seniors with constipation have a higher proportion of suffering from CKD stage 3. Constipation is an independent risk factor contributing to the high prevalence of CKD stage 3 (OR:1.238,95% CI,1.045-1.466). This finding was further tested through a retrospective cohort study that included 4,203 participants with a medium following time of 6.1 years. As a result, 9.5% (n=401) reported to have rapid progression of renal function. After adjustment of confounding factors, the logistic regression analysis indicates that, constipation is an independent predictive variable of rapid renal function decline among aged population. Conclusion Constipation is an independent risk factor for the prevalence of CKD and an independent predictor of rapid renal function decline among seniors in the community. Prevention and treatment for constipation should be taken at an early stage, which may reduce the incidence of CKD and delay the progression of CKD.

Abstract Background and Aims Vascular calcification is known to be an important risk factor in patients with dialysis, However, the comparative study on vascular calcification between peritoneal dialysis (PD) and hemodialysis (HD) is less. The aim of this study was to analyze the presence, risk factors of aortic arch calcification (AAC), and compare the prognosis in maintenance PD and HD patients. Method Using retrospective analysis method, 177 patients with PD and 147 patients with HD were included in the study. The extent of AAC was evaluated by chest X-ray examination. The demographic characteristics and clinical data were collected and compared between PD group and HD group. Binary logistic regression analysis was performed to evaluate risk factors associated with the aortic arch calcification. Results The incidence of AAC in HD group (59.86%) was significantly higher than that in PD group (37.29%). Multivariate analysis showed that age, residual renal function (RRF) and serum phosphate were the independent risk factors for calcification of PD patients and the odds ratio (OR) values were 1.133, 1.039, 0.762 and 18.186, respectively. Similarly, age, RRF, calcium-phosphorus product and LDL were the risk factors of HD patients and their respective OR values were 1.125, 0.509, 2.755 and 3.221. Compared with patients without AAC, the presence of moderate-severe AAC was associated with greater risk of mortality, and the OR values were 17.833 and 20.056 in PD group and HD group, respectively. Conclusion Our findings suggest that the AAC was more common in HD patients. Older age and lower RRF are common independent risk factors for AAC in PD and HD patients. Moderate to severe AAC a ppears to be associated with increased risk of mortality.

Antithrombin III (ATIII), encoded by the gene Serpinc1 , is a serine protease inhibitor in the coagulation cascade and may inhibit inflammation and promote endothelial function. Serpinc1 is down-regulated in Dahl salt-sensitive (SS) rats compared to several rat strains with reduced blood pressure salt-sensitivity. The aim of this study was to investigate the role and the potential therapeutic effect of Serpinc1 /ATIII in salt-induced hypertension. ATIII activity was analyzed in patients with hypertension and the effect of Serpinc1 knockout or overexpression was examined in rat models. For mechanistic analysis, inflammation and endothelial function were examined. Lower ATIII activity is associated with higher blood pressure levels in hypertensive patients (n=90, P=0.015). Hypertension grades are also negatively correlated with ATIII activity (Spearman's coefficient r s =-0.2779, P=0.008). Heterozygous knockout of Serpinc1 in modestly salt-sensitive SS.13 BN26 rats exacerbated salt-induced hypertension (mean arterial pressure 141±5 mmHg in heterozygous knockout rats vs 128±2 mmHg in wild-type littermates after 14 days on a 4% NaCl diet, n=9 in heterozygous group and n= 10 in wild-type group, P<0.05). Serpinc1 overexpression in SS rats using adeno-associated virus (AAV) attenuated salt-induced hypertension (mean arterial pressure 142±7 mmHg in SS rats treated with AAV- Serpinc1 vs 189±13 mmHg in in SS rats treated with AAV-control after 14 days on a 4% NaCl diet, n=6 in AAV- Serpinc1 group and n= 5 in AAV-control group, P<0.05). Mechanistically, Serpinc1 insufficiency significantly increased renal outer medullary interleukin 6 mRNA and decreased endothelial nitric oxide synthase expression and endothelium-dependent vasodilation, while Serpinc1 overexpression had the opposite effect. Treatment of Serpinc1 heterozygous knockout rats with an interleukin 6 receptor antibody attenuated the exacerbation of salt-induced hypertension by Serpinc1 insufficiency. In conclusion, Serpinc1 /ATIII reduces inflammation, improves endothelial function, and attenuates salt-induced hypertension.

Wedelolactone (WED) is commonly used for the treatment of doxorubicin (DOX)-induced kidney damage, but its efficacy is limited by its poor solubility and bioavailability. In this study, we developed a novel delivery system of WED-loaded micelles (WED-M) with Solutol® HS15 and lecithin at an optimized ratio of 7:3 to improve the poor permeability and bioavailability of WED and to enhance its efficacy. The spherically shaped WED-M (particle size: 160.5 ± 3.4 nm; zeta potential: −30.1 ± 0.9 mV; entrapment efficiency: 94.41 ± 1.64%; drug loading: 8.58 ± 0.25%; solubility: 1.89 ± 0.06 mg/ml) has continuous stability over 14 days and a sustained release profile. The permeability of WED-M in Caco-2 cells indicated a significant 1.61-fold higher Papp AP to BL ratio than WED alone. Additionally, pharmacokinetic evaluation of WED-M demonstrated that the bioavailability of WED was increased 2.78-fold. Both HE staining and transmission electron microscopy showed an obvious improvement of pathological damage in WED-M treatment. Moreover, WED-M significantly enhanced the ROS level in mice and MPC5 podocytes. We concluded that using this micelle delivery system for WED could improve its permeability and bioavailability to attenuate DOX-induced oxidative injury in podocytes. This study provided important information on the fact that the micelle delivery system, WED-M, showed a significant improvement of renal damage.

BACKGROUND:In spite of extensive study, the mechanisms for salt sensitivity of BP in humans and rodent models remain poorly understood. Several microRNAs (miRNAs) have been associated with hypertension, but few have been shown to contribute to its development. METHODS:We examined miRNA expression profiles in human kidney biopsy samples and rat models using small RNA deep sequencing. To inhibit an miRNA specifically in the kidney in conscious, freely moving rats, we placed indwelling catheters to allow both renal interstitial administration of a specific anti-miR and measurement of BP. A rat with heterozygous disruption of the gene encoding endothelial nitric oxide synthase (eNOS) was developed. We used bioinformatic analysis to evaluate the relationship between 283 BP-associated human single-nucleotide polymorphisms (SNPs) and 1870 human miRNA precursors, as well as other molecular and cellular methods. RESULTS:Compared with salt-insensitive SS.13BN26 rats, Dahl salt-sensitive (SS) rats showed an upregulation of miR-214-3p, encoded by a gene in the SS.13BN26 congenic region. Kidney-specific inhibition of miR-214-3p significantly attenuated salt-induced hypertension and albuminuria in SS rats. miR-214-3p directly targeted eNOS. The effect of miR-214-3p inhibition on hypertension and albuminuria was abrogated in SS rats with heterozygous loss of eNOS. Human kidney biopsy specimens from patients with hypertension or hypertensive nephrosclerosis showed upregulation of miR-214-3p; the gene encoding miR-214-3p was one of several differentially expressed miRNA genes located in proximity to human BP-associated SNPs. CONCLUSIONS:Renal miR-214-3p plays a functional and potentially genetic role in the development of hypertension, which might be mediated in part by targeting eNOS.

Background. Although the relation between serum uric acid (SUA) and left ventricular hypertrophy (LVH) has been studied for decades, however, their association remains debatable. Methods. This is a retrospective study in which a total of 435 hospitalized Chinese patients with type 2 DKD were enrolled. The subjects were stratified into quartiles according to SUA level. LVH was assessed by two-dimensional guided M-mode echocardiography. Results. There was a significant increase in the prevalence of LVH in patients with type 2 DKD across SUA quartiles (28.9, 26.5, 36.1, and 49.5%; p<0.001). The Spearman analysis indicated that SUA was positively correlated to LVMI and negatively correlated to eGFR. The logistic regression analysis revealed that the odd ratio for LVH in the highest SUA quartile was 2.439 (95% CI 1.265–4.699; p=0.008; model 1) or 2.576 (95% CI 1.150–5.768; p=0.021; model 2) compared with that in the lowest SUA quartile. However, there was no significant increased risk of LVH in the subjects with the highest SUA quartile after adjusting the eGFR (OR = 1.750; 95% CI 0.685–4.470; p=0.242; model 3). Conclusions. In selected population, such as type 2 DKD, the elevated SUA level is positively linked with the increased risk of LVH, but this relationship is not independent of eGFR.

It has been reported that retinol-binding protein 4 (RBP4) is associated to adiposity, insulin resistance, and type 2 diabetes. Meanwhile, circulating RBP4 levels are also affected by renal function. The aim of the present study is to investigate whether serum levels of RBP4 are primarily associated with different stages of chronic kidney disease (CKD) or type 2 diabetes, if there is more potential relevance between RBP4 and renal replacement therapy. The serum levels of RBP4 were assessed by commercial competitive enzyme-linked immunosorbent assay (ELISA) kit in 212 patients with the CKD stages 1—5 and in 24 healthy controls, while its correlation with clinical and metabolic parameters was analyzed. The serum level of RBP4 had a strong correlation with estimated glomerular filtration rate (eGFR) (P < 0.001). Stratified by eGFR and treatment, no more differences in RBP4 serum concentration were detected between type 2 diabetic and non-diabetic subjects [CKD stages 1—5, non-dialysis (ND), hemodialysis (HD) and peritoneal dialysis (PD); P >0.05 for all]. The elevation of RBP4 become higher in HD than in PD and ND in CKD5 patients (P = 0.008 and P = 0.04, respectively), while there was no significant difference between PD and ND groups. Multivariate linear regression analysis demonstrated three independent predictors of eGFR (β = −0.676, P < 0.001), C-reactive protein (CRP) (β = −0.573, P < 0.001) and creatine (β = 0.509, P = 0.024) in the study population. The study results demonstrated that the serum level of RBP4 was negatively related to the eGFR, whether diabetes mellitus (DM) affected the blood concentration of RBP4 or not. And the serum level of RBP4 exhibited significant difference in different renal replacement therapies.

Glomerular mesangial cells (MCs) hypertrophy is one of the earliest pathological abnormalities in diabetic nephropathy (DN), which correlates with eventual glomerulosclerosis. This study aimed to investigate the therapeutic role of miRNA in diabetic glomerular MCs hypertrophy and synthesis of extracellular matrix (ECM). Microarray analysis revealed a significant up-regulation of miR-214 in the renal cortex of diabetic db/db mice, which was confirmed by real-time PCR of isolated glomeruli and primary cultured human MCs. In vitro studies showed that inhibition of miR-214 significantly reduced expression of α-SMA, SM22 and collagen IV, and partially restored phosphatase and tensin homolog (PTEN) protein level in high glucose-stimulated human MCs. Furthermore, we identified PTEN as the target of miR-214 by a luciferase assay in HEK293 cells. Moreover, overexpression of PTEN ameliorated miR-214-mediated diabetic MC hypertrophy while knockdown of PTEN mimicked the MC hypertrophy. In vivo study further confirmed that inhibition of miR-214 significantly decreased the expression of SM22, α-SMA and collagen IV, partially restored PTEN level, and attenuated albuminuria and mesangial expansion in db/db mice. In conclusion, cross talk between miR-214 and PTEN attenuated glomerular hypertrophy under diabetic conditions in vivo and in vitro. Therefore, miR-214 may represent a novel therapeutic target for DN.

Clinical trials shows that remote ischemic preconditioning (IPC) can protect against contrast induced nephropathy (CIN) in risky patients, however, the exact mechanism is unclear. In this study, we explored whether renalase, an amine oxidase that has been previously shown to mediate reno-protection by local IPC, would also mediate the same effect elicited by remote IPC in animal model. Limb IPC was performed for 24 h followed by induction of CIN. Our results indicated that limb IPC prevented renal function decline, attenuated tubular damage and reduced oxidative stress and inflammation in the kidney. All those beneficial effects were abolished by silencing of renalase with siRNA. This suggests that similar to local IPC, renalase is also critically involved in limb IPC-elicited reno-protection. Mechanistic studies showed that limb IPC increased TNFα levels in the muscle and blood, and up-regulated renalase and phosphorylated IκBα expression in the kidney. Pretreatment with TNFα antagonist or NF-κB inhibitor, largely blocked renalase expression. Besides, TNFα preconditioning increased expression of renal renalase in vivo and in vitro, and attenuated H2O2 induced apoptosis in renal tubular cells. Collectively, our results suggest that limb IPC-induced reno-protection in CIN is dependent on increased renalase expression via activation of the TNFα/NF-κB pathway.